Mutations in the presenilins (PS-1 and PS-2) account for .about.95% (75% and 20%, respectively) of all cases of early onset familial Alzheimer's disease (FAD). See R. Sherrington et al., Nature 375, 754-760 (1995); E. I. Rogaev et al., Nature 376, 775-778 (1995); and E. Levy-Lahad et al., Science 269, 973-977 (1995). The presenilins are highly homologous (67% identical), multi-membrane spanning proteins whose function is unknown.
It has been demonstrated that the 46 kDa full-length PS-1 protein is normally processed to 28 kDa and 18 kDa fragments; PS-2 has been reported to be similarly cleaved. See M. Mercken et al., FEBS Letters 389, 297-303 (1996). The predicted cleavage site(s) to account for fragments of this size would be in a region of the protein coded for by exon 8 and exon 9. Exon 8 is a hot spot for mutations leading to FAD. Thus, this region of PS-1, and potentially the cleavage of PS-1 in this region by a presenilinase protease, are important events in the functionality of the protein. A region of PS-1 spanning exons 8-11 has been demonstrated in the present invention to specifically bind a protease, PSP1, whose activity against its endogenous substrates and/or ability to bind to PS-1 are important in the pathology of neurodegeneration associated with AD, frontal lobe dementia, cortical lewy body disease, dementia of parkinson's disease, acute and chronic phases of degeneration following stroke or head injury, neuronal degeneration found in motor neurone disease, AIDS dementia and chronic epileps. Thus, a need exists for provision of the nucleotide and amino acid sequences corresponding to PSP1, for modulators of PSP1 binding to PS-1, and/or modulators of PSP1's proteolytic activity, for methods to identify such modulators and for reagents useful in such methods.